Abstract
BackgroundDiastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, however the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function.MethodsRight atrial appendages from patients with type 2 diabetes mellitus (DM, n = 20) and non-diabetic patients (non-DM, n = 36), all with preserved ejection fraction and undergoing coronary artery bypass grafting (CABG), were collected. From appendages, small cardiac muscles, trabeculae, were isolated to measure basal and β-adrenergic stimulated myocardial function. Expression levels of calcium-handling proteins, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban (PLB), and of β1-adrenoreceptors were determined in tissue samples by Western blot. Collagen deposition was determined by picro-sirius red staining.ResultsIn trabeculae from diabetic samples, contractile function was preserved, but relaxation was prolonged (Tau: 74 ± 13 ms vs. 93 ± 16 ms, non-DM vs. DM, p = 0.03). The expression of SERCA2a was increased in diabetic myocardial tissue (0.75 ± 0.09 vs. 1.23 ± 0.15, non-DM vs. DM, p = 0.007), whereas its endogenous inhibitor PLB was reduced (2.21 ± 0.45 vs. 0.42 ± 0.11, non-DM vs. DM, p = 0.01). Collagen deposition was increased in diabetic samples. Moreover, trabeculae from diabetic patients were unresponsive to β-adrenergic stimulation, despite no change in β1-adrenoreceptor expression levels.ConclusionsHuman type 2 diabetic atrial myocardium showed increased fibrosis without systolic dysfunction but with impaired relaxation, especially during β-adrenergic challenge. Interestingly, changes in calcium-handling protein expression suggests accelerated active calcium re-uptake, thus improved relaxation, indicating a compensatory calcium-handling mechanism in diabetes in an attempt to maintain diastolic function at rest despite impaired relaxation in the diabetic fibrotic atrial myocardium. Our study addresses important aspects of the underlying mechanisms of diabetes-associated diastolic dysfunction, which is crucial to developing new therapeutic treatments.
Highlights
Diastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, the exact underlying mechanism remains unknown, especially in humans
Our study shows for the first time that in human atrial myocardium from diabetic patients with preserved ejection fraction (EF) and coronary artery disease (CAD), the force generation is preserved, whereas the relaxation is impaired, and the right atrial cardiac muscles were unresponsive to β-adrenergic stimulation
Clinical characteristics Diabetes was evident from the high fasting levels of glycated hemoglobin (HbA1c) (58 ± 4 mmol/mol in Type diabetes mellitus (DM) group, normal below 48 mmol/mol) and fasting plasma blood glucose levels (10.0 ± 1.0 mmol/L in DM group, normal below 6.1 mmol/L) (Table 1)
Summary
Diastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function. Impaired cardiac function during diastole is one of the early manifestations of cardiac dysfunction in type 2 diabetes [1], and it makes type 2 diabetic patients prone to developing clinical features of heart failure, with both preserved and reduced ejection fraction (EF) [2,3]. Diastolic function deteriorates progressively over time [4], but the exact mechanisms underlying this clinically important increased stiffness and/or impaired relaxation, especially in diabetes, remain unclear. As impaired diastolic function limits cardiac performance during exercise [11] and leads to an intolerance to tachycardia [12], it is crucial to determine how relaxation is challenged by β-adrenergic stimulation, one of the most important extrinsic physiological stimulus of the myocardium
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